1. Field of the Invention
The present invention relates to hydrogels effective for the treatment of atopic dermatitis, comprising biocompatible polymers, polyalcohols, and extracts from medicinal herbs.
2. Description of the Related Art
Atopy is an allergic hypersensitivity that predisposes a person to certain allergic responses, such as atopic dermatitis. Atopic dermatitis is a chronic/inflammatory skin disease, which is the hereditary predisposition to allergies or hypersensitivity. It is a familial and chronic disease with characteristic forms and distributions of skin lesions. Atopic dermatitis is typically found in people having an atopic predisposition. Its symptoms start as congenital fever from infancy, especially in babies around two months after birth. About 50% of patients are reported to suffer from atopic dermatitis from two years after birth or earlier. Atopic dermatitis occurs, for the most part, 5 years after birth at the latest. A medical rarity is the start of atopic dermatitis in adults. Its symptoms are relieved or disappear over time. It is known that the condition of half of the patients changes for the better 2 years after birth or earlier.
Atopic dermatitis is largely typified by pruritus, xerosis (dry skin), and eczematous lesions. Scratching the itchy spots may result in skin damage which gives rise to an increase in the risk of bacterial infection. Xerosis aggravates pruritus, which causes the person to scratch. Scratching or rubbing the skin can make the itch and rash of atopic dermatitis worse. Therefore it is important to prevent the skin from drying out upon treatment for atopic dermatitis.
The exact pathological cause of atopic dermatitis remains unknown. It is believed that together with hereditary predisposition, immunological and non immunological mechanisms are implicated in atopic dermatitis. Extrinsic atopic dermatitis, from which most patients suffer, is caused by the presence of elevated levels of total and allergen-specific IgE in the serum of the patients. Primary immune responses based on T-cell abnormality as well as or rather than secondary immune responses to specific allergens are involved in the pathological mechanism of atopic dermatitis, as cell-mediated immunity in patients with atopic dermatitis is known to be related to the elevated level of IgE.
In up to about 80% of patients with atopic dermatitis, immune disorders are detected. Such patients tend to show hypersensitivity to cutaneous infection by viruses and dermatophytes and hyposensitivity to contagious allergens. In the past, deficiency in T-cell maturation and a decrease in the number of CD8+ regulatory T-cells were reported. However, it was recently observed that CD4+ T-cells play a more important role in the mechanism of atopic dermatitis. T-cells which secrete IL-4 and IL-5, inducers or promoters for the production of IgE from B cells, and IL-6, an amplifier for the production of IgE from B cells, are Th2 cells, among CD4+ T-cells. It is found that the level of Th2 cells is higher than that of Th1 cells in the skin of atopic dermatitis patients. These cytokines are known to stimulate mast cells, macrophages and basophils to induce the secretion of histamine, leukotriene, prostaglandin and nitrogen monoxide (NO), which are inflammation mediators responsible for the inflammatory response of the skin.
In consideration of the pathology, mechanism and symptoms known thus far, extensive attempts have been made to develop therapeutics for atopic dermatitis. As a result, natural or synthetic immunosuppressants, steroids, and anti-histamine agents are currently commercialized. Conventional steroid agents and anti-histamine agents for the treatment of atopic dermatitis relieve the symptoms of atopic dermatitis temporarily, but not permanently.
Reversing xerosis is one of the key elements in the treatment of atopic dermatitis. Using emollients is considered standard therapy in treating patients with AD. However, conventional emollients, for example, moisturizers containing beeswax, glycerin, propylene glycol, and fatty acids, do not show excellent moisturizing effects due to their inability to effectively regulate moisture evaporation.
One of the uses for hydrogels is as a dressing for healing of burns or for dermal regeneration of wounds. For use for this purpose, hydrogels must have a water content of at least 60%. Also, being biocompatible with blood, humoral fluid and bio-tissues, these hydrogels can be applied to contact lenses and cartilage.
The preparation of such hydrogels applicable for these uses is based on a polymer which can be formed into hydrogel. Typically, hydrogel has a three-dimensional network structure of polymer chains containing hydrophilic functional groups such as carboxylic group (—COOH), amide group (—CONH2), and sulfonyl group (—SO3H), and is water-insoluble, but swells in aqueous solution. In greater detail, hydrogels, which have an insoluble network of polymer chains, absorb water thanks to their characteristic structures accounting for capillary and osmotic phenomena, but are insoluble in water due partly to their electrostatic and lipophilic interaction between polymer chains and mainly to covalent bonds between polymer chains.
Typically, hydrogels are prepared from synthetic polymers, naturally occurring polymers or combinations thereof. Examples of the synthetic polymers include hydrophilic synthetic polymers such as polyvinyl alcohol, polyethylene oxide, polyhydroxyethylmethacrylate, polyvinylpyrrolidone, and so on, but are limited thereto Naturally occurring polymers useful in the preparation of hydrogels may be found among carrageenan, gelatin, agar, alginate, collagen and chitosan.
The preparation of hydrogels may resort to chemical methods or radiation methods. Keen attention is paid to radiation methods because they have the advantage over chemical methods in various aspects. First, because radiation methods employ neither crosslinking agents nor initiators for the crosslinking of polymer chains, in contrast to chemical methods, there is no need to remove crosslinking agents and initiators out of fear of toxicity. Radiation can give rise to both crosslinking and sterilization. Also, radiation methods, which require no heat, make it possible to crosslink polymers even in a frozen state. Even the physical properties of the final product hydrogels can be freely adjusted with a radiation dose.
Various methods for preparing hydrogels are documented in the literature. U.S. Pat. No. 5,389,376 discloses a method of preparing hydrogel dressings for wound healing through radiation crosslinking. In this method, polyvinylpyrrolidone is mixed with agar and polyethylene oxide, followed by radiation to crosslink the polymers. Of course, this method enjoys the advantage of the radiation method, that is, effecting both crosslinking and sterilizing simultaneously, but polyvinylidone and agar are poorly miscible, resulting in a reduction in the strength of the final product hydrogels.
U.S. Pat. No. 5,480,717 discloses processes in which a hydrogel laminate is formed by casting onto a polymeric adhesive-coated substrate an aqueous solution of hydrophilic polymer, and then exposing this composite to ionizing radiation. The hydrogel laminate is weak in hydrogel strength, but its excessively strong adhesiveness causes polyvinylidone to remain on the wound when the laminate is detached therefrom.
Japanese Patent Laid-Open Publication No. Hei. 9-267453 describes a laminate based on a polyvinyl alcohol substrate having improved physical properties. However, the simple radiation of this patent cannot bring about a great improvement in the physical properties of the laminate. In addition, two rounds of radiation are required, because the laminate cannot be packed while maintaining the integrity of the form unless radiation is conducted.
Korean Patent Laid-Open Publication No. 2001-0086864 discloses a method of preparing hydrogel dressings for wound healing, comprising: mixing a synthetic polyvinylidone polymer with chitosan, chitosan and polyethylene oxide, or sodium alginate and polyethylene oxide to give an aqueous solution (step 1); molding the aqueous solution of step 1 into a sheet form (step 2); packaging the sheet of step 2 (step 3); and radiating the packaged sheet of step 3 (step 4). Another method of preparing a hydrogel for wound healing is disclosed in Korean Patent Laid-Open Publication No. 2003-0060458, which comprises coating on a membrane either an aqueous solution of a biocompatible polymer selected from among polyvinylidone, polyvinyl alcohol, chitosan and combinations thereof, or an aqueous solution of a mixture of the biocompatible polymer and glycerin, freezing and thawing the coating to form a pre-hydrogel; packaging the pre-hydrogel molded on the membrane with a sheet; and radiating the packaged pre-hydrogel. Korean Patent Laid-Open Publication No. 2004-0085646 suggested a hydrogel dressing prepared from a composition comprising polyvinylidone, polyalcohol and carrageenan, a preparation method thereof using a tray and radiation, and a dressing for wound healing and a cosmetic skin pack using the same.
The available time of these hydrogels is too short. When exposed to air for 12 hours, these hydrogels, however, evaporate and thus cannot function as therapeutics for wounds.
A solution to these problems was proposed in Korean Patent No. 61237, which discloses a hydrogel for wound healing, prepared by coating an aqueous solution of a biocompatible polymer selected from among polyvinylidone, polyethyleneglycol, carrageenan and combinations thereof on an ethylene vinylacetate(EVA) copolymer film, an ethylene vinylalcohol(EVOH) copolymer, a very low density polyethylene(LDPE) film or a polyurethane membrane to form a pre-hydrogel, and crosslinking the biocompatible polymer with radiation to give a hydrogel containing a water evaporation-preventive layer.
This hydrogel can prolong the release of water for about 60 hours, but the lack of air permeability of the film employed in the hydrogel makes it impossible to apply the hydrogel to the treatment of atopic dermatitis.
Leading to the present invention, intensive and thorough research into hydrogels usefully applicable for the treatment of dermatitis, conducted by the present inventors, resulted in the finding that an extract from medicinal plants which is effective in the treatment of dermatitis, especially contact dermatitis and atopic dermatitis, can be released for a suspended period of time when it is associated with a network structure of polymer chains, and that, when supported by a laminate of a hydrophilic non-woven fabric sheet and an air-permeable polyethylene film, the hydrogel can retain water for a suspended period of time, thereby allowing the skin to be kept wet during the application thereof to the skin. Therefore, the hydrogel significantly relieves pruritus and prevents secondary wounds attributed to scratching.